Synthesis of carboxylic acids



on CARBOXYLIC ACIDS Fred W. Hoover, Pembrey, near Wilmington, Del., as-

signor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation ofDelaware No Drawing. Filed May s, 1951, Ser. No. 656,754 15 Claims. 01. 204-154 This invention relates to carboxylic acids and has for its principal object provision of a novel method of synthesizing such acids.

It has been reported heretofore that radiolysis' of aqueous formic acid yields hydrogen and carbon dioxide as the principal products [Fricke et al., J. Chem. Phys., 6, 229 (1938)]. It has also been found that exposure of aqueous formic acid to ionizing radiation may yield other organic acids and formaldehyde as well as some hydrogen and carbon dioxide [Garrison et al.', J. Am. Chem. Soc., 74, 4216 (1952)]. ...It is nowfound that formic acid, upon irradiation therewith, preferentially carboxylates C-H groups in which the carbon is not also-a carbonyl carbon, i.e., not doubly-bonded to oxygen. When formic acid is mixed with a second organic compound containing a C--H group with a noncarbonyl carbon and irradiated, it consequently carboxylates the second compound preferentially to itself. This preferential reaction of formic acid with the second organic compound can be employed to provide a novel and general synthesisjof carboxylic acids. In the preferred practice of the invention, an intimate mixture of formic acid and the second compound having a carbon-hydrogen bond (usually a solution) in a mole ratio of formic acidzmole equivalent of carboxylated CH bond in the second compound-in the range of about 1:3- 3:l, the mixture containing no more than about by weight of any third material such as water, is subjected to ionizing radiation having an energy of at least 50 electron volts, formic acid being maintained in the reaction mixture throughout the time of irradiation. The resulting carboxylated 'material is then generally separated from the reaction mixture. F Organic'compounds suitable for carboxylation with formic acid according to the presentinvention are those containing at least one C-H group. With all such compounds the process of this invention produces the reaction:

aryl aliphatic or aromatic hydrocarbons, alcohols, ethers, aldehydes, ketones, amines, nitriles and the like. Preferred compounds for carboxylation according to. this invention are the hydrocarbons, i.e., alka'nes, alkenes, alkynes and aromatic substituted derivatives of same, as

. derivatives are obtained when the reactants are employed.

. 2 containing more than carbons, e.g., paraflin 'wax. In usage preferred from the standpoint of the value of the products, the carbon compounds will usually contain not more than 18 carbons.

The requirement'rthat the composition irradiated consist at least 90% of a mixture of formic acid and the organic compound being carboxylated is .based on the.

fact that minor amounts of extraneous materials are, readily tolerated by the reaction, whereas substantial amounts (i.e., in excess of 10% by weight) of extraneous materials, particularly water, lead to excessive production of by-products, e.g., hydroxylated compounds, and are to be avoided.

The molar ratio of formic acid to the organic compound being carboxylated is restricted to the range of 3:1 to 1:3 because best yields of isolatable carboxylated in quantities not too far removed from stoichiometric values. 7

It is essential for the formic acid and organic com-.

pound to be in intimate contact during irradiation in the process of this invention. Since formic acid is an excellent solvent, it is most convenient to accomplish this by dissolving the organic compound in formic acid and irradiating the mixture under temperature and pressure. conditions in which formic-acid is liquid. However,

' other means for providing intimate contact may be employed. if under the conditions of irradiation the organic compound is a solid, it may be used in finely-di vided form and suspended in liquid formic acid by means of suitable stirring. Gaseous organic compounds can be dispersedv in liquid formic acid by vigorous agitation or by bubbling gas through the formic acid and recycling the gas.

By operating at temperatures in excess of 100 .C. it is possible to employ both the formic acid and the organic compound as gases.' This permits excellent contact, al- -though formic acid is somewhat unstable under these conditions and excessively high temperatures, i.e., 200 C. and above, .are to be avoided. Low temperatures, such as -l00 C. and below, may be employed in this process, but, in general, ambient temperatures are satisimpinge upon the formic acid mixture. The charged well as aromatic hydrocarbons .of the benzene, naph- 'thalene, anthracene, etc., series. For practical purposes,

organic compounds free of carboxyl groups represent another preferred group of starting materials forthis inlinkage, it willgenerally not be. applied to compounds particles may be'accelerated by means of a suitable voltage gradient, using such devices as a cathode ray tube, resonant cavity accelerator, a Van de Graaif accelerator, a Cockcroft-Walton accelerator, or the like, as is well known to those skilled in the art. Neutron radiation may be produced by suitable nuclear reactions, e;g., bombardment of a beryllium target with deuterons or alpha-particles. In addition, particle radiation suitable for carrying out the process of the invention may be' obtained from an atomic pile, or. from radioactive isotopes or from-other natural or artificial radioactive materials. a

By ionizing electromagnetic radiation is meant radiation 1 of =the type produced when a metal target: (e.g.,

,tungstenlis bombarded-by electrons possessing appropriate energy. Such radiationis conventionally termed X-ra'y, In addition to X-rays produced as indicated tained. from a nuclear reactor. (-fpile.) orfrom natural Patented June 14, taco or artificial radioactive material. cases the radiation is conventionally termed gamma rays. It is recognized that the energy characteristics of one formofionizing radiation can be expressed iriterms which are appropriate forfanother form. Thus, one may express the energy of either the particles of radiation commonly considered as particle radiation'or of the: photons of radiation commonly considered as wave or electromagnetic radiation in electron volts (e.v.) 'or million electron volts (m.e.v;). ln'the irradiation process of this invention, radiation. consisting of particles or photons having an energy of 50 e.v and over-may be employed and particles or photons having anenergy of 0.1 'rn.e.v. and over arepreferred. With radiation of this type, carboxyl'ation of compounds with'formic acid can be obtained with a minimum length of exposure to the r'adiationjpermitting maximum efficiency in utilization of the radiation. .Particles orpho'tons withan energy equivalent. of 0.5-4 m.e .v. are the most useful from a practical standpoint, although radiation. with energies of m.e.'v. and higher may be employed.

Using a minimum dosage of at least 10 rads is necessary since lower dosages do not give efiective carboxylation. The rate of carboxylation usually increases with decreasing beam intensity. Dosages. as high as 10 to' 10 rads and higher may be employed. The exposure may be carried out in one slow pass, orin several faster ones and may be conducted at any convenient rate of energy input. One rad is the-quantity of radiation which willresult-in an.absorp tion.of 100 ergs .pergram'of irradiated material. The carboxylic acidproduced by' this invention may be isolated "directly byfdistillation, fractional crystallization, chromatography, selective extraction with a suitable organic solvent or the like; Alternatively, thexacid'may be first converted to a derivative, such as a salt, ester,

. hydrochloride (of amino acids) orthe like, and isolated in the form of the derivative by any of the'usual techniques known'in the art.

In, the following examples parts are by weight and pressures are ambient atmospheric unless otherwise indicated. 7 7

7 EXAMPLE 1 iiiixmjre'or 230 of 98% formic'acid and 230 g. of benze'new'as charged 'into a horizontal'glass cylinder'59 cm. long, 45 in outside diai'neter and 43 mm. in inside'diameter. I A spiral stainless steel "g auie stirrer ran the Ien'gth of the vessel, which washalf-irnmersed in an ice bath. While a slow stream of nitrogen passed through the. vessel and the mixture was vigorously stirred, a SOD-watt beam of 2-m.e.v. electrons'was impinged on the outer surface'of the vessel for sixty minutes. The absorption of electronic energy by the'inixtureduring this time was' about 9X10 watt-second. Material volatile at 45"/20 was then removed by'distillation, leaving 13.3 g. of thick brown 'oil. The oil was taken up in 'chloroformjthe' chloroform was extracted with dilute aqueous sodium hydroxide, and thealkaline extract was acidified and extractedseve'ral times with chloroform. Ihechloroform extract was dried, concentrated to a small volume by distillation, and chromatographed on :silicic acid by the procedure of Marvel and Bands, J. Chem. Soc., 72, 2642 611950). By means of the chrom atogjraphy, 0.10 g. of benzoic acid wasi solated. It was identified by conversion to j'p-bromophenacyl ben'zoate, Ml. 120421? C. both alone and when mixed with an authentic sample. j I EXAMPLE 2 I r A mixture of 98 g; of; 98% formic-"acid ahd g.

'of cyclohexane'wa's irradiated' inthe apparatus described in'Exam'ple 1" using a SOO-Watt beam of- 2-ni'..v;"eleet'rons In all of these latter ass i em" for '60 minutes. 1 Theabsorption' oflelec'tronic energy" by "chromatography as tinj Example "-1,'"and' 0.065 :g: of cyclo- 4 hexanecarboxylic acid was isolated. It was identified by the melting point (9192 C.) and infrared absorption spectrum of its p-bromophena'cyl ester, both of which were identical with those of authentic p-bromophenacyl cyclohexanecarboxylate.

EXAMPLE 3 A mixture of 40 ml. of 88% formic acid and 25 g. of paratfin wax 'ivas "spread in 'a glass "dish "one inch deep and covered with aluminum foil. The mixture was then irradiated with- 2 mze.-v.' electrons through the foil until 1650 watt 'sec. 0f "nergywas "absorbed by the-mixture. The product was dissolved in cyclohexane. The infirared sweetness-scream ofthissolutibrfshowedtliat"carboxyl groups had been'introduced'on the paraflin chains. 7

In the following table, section A showsorganic compounds which when irradiated in the presence of formic acid yield the indicated earboxylic acid product, as in Examples I: ah II. j secasn B shows compounds 'v'vhich when irradiated in -the presence "of formic acid 'yield "a Compound Irradiated with Oarboxylic Acid Producfls) Formic Acid SecttonA: 1

.rnethane H ,aceticactd.

ethane... propionic acid. h V 'neppentane 3,3-dimethylbutyric' acid. math alcoh glycolic acid. methyl chloride chloroacetic acid. methyl fluoride 'fluoroacetic acid.

' .methylamine glycine, U v

,trimethylaminen N,N-dimcthylglycine.

' acetonit'rile cyanoacetic acid. SectlcnB: 1

- Propane"... ,butyrlc acid and isobutyric acid.

isobutaue.. 'pl'valic acid and isovalcric acid.- naphthalen amaphthoic acid and fl-naphth oic acid. ethyl alcohol. lactic acid and hydracryli 0 acid. isopropyl' alcohol; a-hydroxy isobutyric acldand 3-h ydr'oiry- .b t 'ic aci diethyl ether '2 -ethoxypropionic acid and 3-ethoxypropionic acid.

" ethyl bromide 'Z-bziomopropionic acid and 3-brornopro pionicacid. v

. p epion ac 1 7 methyl acetate mpnomethyl ester of ma-lonic acid and acetoxyacetic acid. Be lqnQs.

heptane... octanqic acid and isomers.

' propylene. vinylacetic acid and isomers.

toluene. phenylaceticjacid and-toluic acids. l-hexy 2-ethyqy a aric c d d isomersphenylacetylene p-ethynylbenzo'ie acidand isomers.

2,4,4-trimethylpentanol 2;liiydroxy 3, 5;5-trimethy1caproic acid and somers. v

" bcnzyl alcoholmandelic acid and isomers.

. d ibenzyl ether a-benzyloxy luic acid and isomers.

propyl iodide 2-iodobutyric acid and isomers.

chlorobcnzene p-chlorobenzoic acid and'isomers. i i-bromonaphthalene. 1-bromo-4-napl1thoic acid and isomers. benzyl chloride chlorophenylacetic acid and isomers. benzaldehydc.-. p-tormylbenzoic acid and isomers. 4-heptanone;; i iieptanone-i'acarbox-y-lic acid and isomers. benzophenone i-benzcphenonecarboxylic acid and isomers.

I Jpi eridine- ZcarbOxYlic acid and isomers. I I morpholinea-cajrbcxylic acid andisoniers.

r. Y so shnw 1 beuzoriitri1e...,... 'p-jc'yanobcnzfolc a'cidand isomers. V I

1 phenylacetonitrile. 2-cyano-2-phenylacetic acid and isomers. nitrobenzene m-nitrobenzoicacid-and isomers. I

bound'solly-by neassenaea'claims. v

Thev 'odifiieiits of'he invention inwhich,'an'iexclusiv e property .or privilege. is claimed are-definedhs followsz p 1. In the synthesis of a carbo'xylicaid,thesteps'comprising (1) intimately mixing a first compound containing a carbon-hydrogen bond, said carbon being noncarirradiating the resulting mixture with at least 10 rads of ionizing radiation having a minimum intensity of 50 electron volts at a temperature between about 100 and +200 C. p

2. The invention of claim 1 in which the carbon attached to the hydrogen possesses no double bond other than a double bond to another carbon.

3. In the synthesis of a carboxylic acid, the steps comprising (1) intimately mixing a hydrocarbon with formic acid and (2) irradiating the resulting mixture with at least rads of ionizing radiation having a minimum intensity of 50 electron volts at a temperature between about -100 and +200 C.

4. The invention of claim 3 in which the hydrocarbon is aliphatic.

5. The invention of claim 3 in which the hydrocarbon is cycloaliphatic.

6. The invention of claim 3 in which the hydrocarbon is aromatic.

7. The method of replacing with a carboxyl group a hydrogen atom on a carbon atom joined thereto but free of double-bonded connection with oxygen which comprises irradiating the compound containing said carbon atom with at least 10 rads of ionizing radiation having a minimum intensity of 50 electron volts in admixture with formic acid at a temperature between about -100 and +200 C.

8. The invention of claim 1 wherein said first compound contains no more than 30 carbons.

9. The invention of claim 1 wherein said first compound contains no more than 18 carbons.

10. The invention of claim 3 wherein the hydrocarbon contains no more than carbons.

11. The invention of claim 3 wherein the hydrocarbon contains no more than 18 carbons.

12. The invention of claim 7 wherein the compound containing said carbon atom contains no more than 30 carbons.

13. The invention of claim 7 wherein the compound containing said carbon atom contains no more than 18 carbons.

14. The process of producing benzoic acid which comprises irradiation with at least 10 rads of ionizing radiation having a minimum intensity of electron volts an intimate admixture of formic acid and benzene at a temperature between about C. and +200 C.

15. The process of producing cyclohexanecarboxylic acid which comprises irradiating with at least 10 rads of ionizing radiation having a minimum intensity of S0 electron volts an intimate admixture of formic acid and cyclohexane at a temperature between about 100 C. and+200 C.

References Cited in the file of this patent UNITED STATES PATENTS 2,823,216 Moote et a1. Feb. 11, 1958 

1. IN THE SYNTHESIS OF A CARBOXYLIC ACID, THE STEPS COMPRISING (1) INTIMATELY MIXING A FIRST COMPOUND CONTAINING A CARBON-HYDROGEN BOND, SAID CARBON BEING NONCARBONYL, WITH THE SECOND COMPOUND FORMIC ACID AND (2) IRRADIATING THE RESULTING MIXTURE WITH AT LEAST 10**4 RADS OF IONIZING RADIATION HAVING A MINIMUM INTENSITY OF 50 ELECTRON VOLTS AT A TEMPERATURE BETWEEN ABOUT -100* AND +200*C. 